Hernia repair grafts having anti-adhesion barriers

ABSTRACT

Materials for soft tissue repair, and in particular, material for hernia repair. These materials may be configured as an implant, such as a graft, that may be implanted into a patient in need thereof, such as a patient having a hernia or undergoing a hernia repair surgical procedure. These grafts may include a first layer comprising a substrate (e.g., mesh) and a second layer comprising a sheet of anti-adhesive material. The layers may be attached with a plurality of relatively small attachment sites that are separated by regions in which the two layers are not attached, to provide a highly compliant graft.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation of U.S. patent applicationSer. No. 15/814,275, filed Nov. 15, 2017, titled “HERNIA REPAIR GRAFTSHAVING ANTI-ADHESION BARRIERS,” now U.S. Pat. No. 10,564,485, which is acontinuation of U.S. patent application Ser. No. 15/498,409, filed Apr.26, 2017, titled “HERNIA REPAIR GRAFTS HAVING ANTI-ADHESION BARRIERS,”now U.S. Pat. No. 9,820,843, which claims priority to U.S. ProvisionalPatent Application No. 62/327,494, filed on Apr. 26, 2016, titled“ADHESION BARRIERS SEWN ON TO OR SEWN INTO IMPLANTABLE SOFT TISSUEREPAIR SUBSTRATES,” each of which are herein incorporated by referencein their entirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference in their entirety to the sameextent as if each individual publication or patent application wasspecifically and individually indicated to be incorporated by reference.

FIELD

The apparatuses (e.g., devices and systems, including grafts) andmethods described herein relate generally to the field of soft tissuerepair. More particularly, described herein are graft materials for softtissue repair that include an adhesion barrier that inhibits theformation of post-surgical adhesions while advantageously matching thebiomechanical properties of the tissue during healing and recovery.

BACKGROUND

Adhesions are fibrous bands of connective tissue that form betweentissues and organs in the body that are not normally connected together,or that form in a way that is different from the normal connectivetissue anatomy between tissues and organs in the body. Adhesionscommonly form after surgery on the abdomen or the pelvic regions, thoughpost-surgical adhesions may form anywhere in the body. In certain cases,adhesions may cause complications such as pain or obstruction of theorgans to which they connect.

Adhesions generally begin forming shortly after surgery, and continue todevelop thereafter. There are no known treatments to reverse adhesionformation. If adhesions lead to complications in the patient, thetypical treatment is to remove them surgically. The best approach toadhesion management is prevention.

Various products are on the market for prevention of adhesion formation.These products are not 100% effective, though their use fairlyconsistently substantially reduces adhesion formation. These productstake on many forms, such as gels and pastes that are applied to surgicalsites within the body, and are gradually resorbed over a the course of afew days.

Another anti-adhesion product is a physical barrier, such aspolytetrafluorethylene membranes. The barriers need not be permanentimplants and, to this end, oxidized regenerated cellulose (ORC) sheetsare commonly implanted within surgical sites. These ORC sheets areresorbed over the course of a few days, and are typically well-toleratedby patients.

Adhesions may be particularly troublesome when repairing soft tissue,such as a hernia, in which success and recovery of the procedure in boththe short and long term may be determined in part by the biomechanicalresponse of the graft used to repair the tissue. The compliance of thegraft used to repair the tissue may largely affect outcome of theprocedure; it is generally better to match the compliance of the tissue,and avoid both over-compliant and under-compliant implants. However thecompliance of the implant may change over time, in part because of thetissue response, including the presence of adhesions. Adhesions maychange the compliance of the implant.

Hernia repair surgery, which is a form of abdominal or pelvic surgery,often induces adhesion formation. Certain hernia repair proceduresinvolve the implantation of synthetic or biologic mesh materials thatsupport biologic loads at the site of herniation while the body repairsitself. But over time, these implanted hernia repair substrates maybecome progressively infiltrated with and covered with scar tissue, andthemselves become a source of adhesions.

There remains a need for adhesion prevention and control, particularlywith respect to hernia repair surgery. Further, there is generally aneed for hernia repair grafts that are sufficiently compliant and thatmaintain their biomechanical properties, including compliance, over timewhile implanted into a patient.

SUMMARY OF THE DISCLOSURE

The present invention relates to materials for soft tissue repair, andin particular, material for hernia repair. These materials may beconfigured as an implant, such as a graft, that may be implanted into apatient in need thereof, such as a patient having a hernia or undergoinga hernia repair surgical procedure. Advantageously, these materials (andany apparatuses such as devices and systems, including grafts) areparticularly well suited for surgical implantation over time in repairof a body wall cavity, and may have biomechanical properties, andparticularly a compliance, that matches that of a patient's body bothinitially (e.g., immediately upon implantation) and over time followingimplantation. Further, these materials (and any apparatuses such asdevices and systems, including grafts) may prevent tissue attachments.

The apparatuses (e.g., grafts, implants, etc.) may comprise a substratematerial that may be a mesh. The substrate (mesh) may be a biotextile,medical textile, or both a biotextile and medical textile. Theseapparatuses may also include an adhesion barrier that is attached atdiscrete locations (e.g., sewn or embroidered into the substrate mesh orsewn onto the substrate mesh) while still allowing sliding between thesubstrate mesh and the anti-adhesion layer (adhesive barrier) at regionsadjacent and/or between the discrete adhesion locations. The substratemesh may comprise an extracellular matrix, or a scaffold, or a herniarepair scaffold, patch, or mesh; the substrate is typically arranged inan open-cell mesh, and may be referred to herein as a “mesh”. Thesubstrate may comprise a biocompatible film. The substrate (e.g., mesh,or mesh plus embroidered pattern on the mesh, etc.) may be referred tocollectively as a first layer.

Any of the substrates described herein may be a mesh formed of a firstmaterial that is non-bioabsorbable (e.g., a non-bioabsorbable mesh).These materials may also include a first pattern of a filament (e.g.,thread, wire, braid, monofilament, multi-filament, etc.) that is sewn orembroidered into the mesh. This first pattern may be embroidered with abioabsorbable material or, if the mesh is bioabsorbable, a materialhaving a second bioabsorbable profile; e.g., that is absorbed morequickly than the mesh material. The first pattern may be a grid or arrayof lines of stitches that are parallel; in some variation the firstpattern may comprise a plurality of sub-patterns that are arrangedoffset from each other and overlapping. The material forming the firstpattern, and the overall first pattern, may have a lower compliance thanthe mesh. Thus, the final compliance of the substrate may be thecompliance of the mesh and the first pattern embroidered onto the mesh.

The compliance (e.g., flexibility) of a material may refer to themechanical property of the material undergoing elastic deformation whensubjected to an applied force. It is the reciprocal of stiffness.Compliance may be described as a percent compliance strain. Materialsthat deform easily are said to be compliant.

In any of the apparatuses (materials, grafts, etc.) described herein,the adhesion barrier may comprise one or more layers of an adhesionbarrier material. The substrate may comprise one or more, or a pluralityof layers of the biotextile and/or medical textile. The material maypreferably be an extracellular material material (ECM), such asextracellular matrix derived from one or more of the dermis,pericardium, peritoneum, intestine, stomach, or forestomach. Theadhesion barrier may be referred to collectively as a second layer.

The second (anti-adhesion layer or adhesion barrier layer) layer may beattached to the first (substrate, e.g., mesh or mesh and embroideredpattern) layer in a manner that does not substantially change thecompliance. In practice, this may mean that the compliance of the firstand second layers separately or when loosely stacked on top of eachother, is not changed more than a few percent when attached together asdescribed herein. For example, the compliance of the material when thefirst (mesh or mesh and first embroidered pattern) and second (e.g.,anti-adhesion layer) are attached together by a pattern, e.g., a secondpattern or “attachment pattern”, of discrete attachment sites may bewithin 20% or less (e.g., within 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%,11%, 10%, 9%, 8%, 7%, 6%, 5%, or less, such as within 10% or less, orwithin 15% or less, etc.) of the compliance of either the first layeralone or the second layer alone, or a loose stack of the first andsecond layer (e.g., the two stacked onto each other as layers that arenot attached).

The discrete attachment sites may be stitches connecting the first layerto the second layer, or they may be chemical or material adhesivesbetween the two layers in small, discrete locations, such as an adhesiveor glue material that is biocompatible and adheres the first (e.g.,mesh, mesh that is embroidered, etc.) layer to the second (e.g., ECM)layer. The adhesive may be any appropriate biologically compatibleadhesive. The discrete attachment sites may refer to relatively smalldiameter regions which may be regularly shaped or irregularly shaped.When the discrete attachments are stitches sewn between the two, thediscrete attachment sites may have a diameter of the stitching material(e.g., fiber, thread, yarn, etc.). For example, the discrete attachmentsites may have a diameter of between about 0.001 inch and 0.20 inches(e.g., between about 0.001 inches to about 0.010 inches, between about0.001 to about 0.060 inches, etc.).

When the adhesion barrier is sewn or embroidered to the substrate, thesewing or embroidery may comprise a stitch pattern (e.g., an attachmentpattern) comprising at least one filament, thread, or yarn comprising anadhesion barrier material. Note that these stitch patterns may bepatterns of discrete attachment sites arranged in the pattern; theadhesion site may refer to connection or stitch between the two layers.Thus any of these stitch patterns may refer to the pattern of discreteattachment sites between the two layers (e.g., the substrate/mesh layerand the anti-adhesion layer/ECM). The stitch pattern may comprise aplurality of straight lines oriented along one or more axes of thesubstrate. A subset of straight lines oriented along different axes ofthe substrate may intersect, and may form a grid pattern. The stitchpattern may comprise a plurality of parallel lines. The stitch patternmay comprise a plurality of lines arranged in a zig-zag. A subset of thelines in a zig-zag may comprise a different amplitude, frequency, oramplitude and frequency relative to another subset of the lines in azig-zag in the stitch pattern. The stitch pattern may comprise aplurality of lines arranged in a pattern comprising a plurality ofcurves, including a wave pattern (e.g., a sinusoidal wave) or anoscillating line pattern. A subset of the lines in a curve pattern maycomprise a different amplitude, frequency, or amplitude and frequencyrelative to another subset of the lines in a curve in the stitchpattern. The stitch pattern may be continuous or comprise breaks orinterruptions. The stitch pattern may comprise a corner-lock stitchpattern. The stitch pattern may comprise an upper filament, thread, oryarn and a lower filament, thread, or yarn. The upper filament, thread,or yarn may comprise a larger diameter relative to the a lower filament,thread, or yarn, or may comprise substantially the same diameterrelative to the lower filament, thread, or yarn, or may comprise asmaller diameter relative to the lower filament, thread, or yarn. Theupper filament, thread, or yarn and the lower filament, thread, or yarnmay comprise any one or more of chitosan, hyaluronic acid, icodextrin,fibrin, poly(L-lactide-co-D,L-lactide)/polylactic acid,polytetrafluoroethylene, or oxidized regenerated cellulose, includingany combination thereof.

In general, the attachment between the first layer (substrate layer,e.g., mesh) and the second (anti-adhesive) layer may be configured toflexibly attach the two layers, so that the attachment of the two layersdoes not change the compliance more than a nominal (e.g., 15% or less)amount. This flexible attachment may be achieved (at least in part) byincluding regions between the discrete attachment sites that are notattached, so that the first layer and second layer may move (e.g.,slide) relative to each other as the material is bent or pulled. Forexample, the discrete attachment sites may be separated by a distance ofgreater than 0.02 inches (e.g., 0.5 mm) (e.g., greater than 0.01 inches,0.02 inches, 0.03 inches, 0.04 inches, 0.05 inches, 0.06 inches, 0.07inches, 0.08 inches, 0.09 inches, 0.1 inches, 0.2 inches, 0.3 inches,0.4 inches, 0.5 inches, etc.). The discrete attachment sites may beseparated by a distance of between 0.02 inches and 1.2 inches (e.g.,between 0.5 mm and 30 mm) (e.g., between 0.01 inches and 1.5 inches,between 0.01 inches and 1.2 inches, between 0.01 inches and 1.1 inches,between 0.02 inches and 1 inch, between 0.02 inches and 0.9 inches,between 0.02 inches and 0.8 inches, etc.). The density of the discreteattachment sites may be uniform or non-uniform. As mentioned above, thediscrete attachment sites may be distributed in a pattern such as a grid(or overlapping grids). The density (e.g., average density) ofattachment sites may be relatively low. For example, the density ofattachment sites may be less than about 10 attachments/mm² (e.g., lessthan about 15 attachments/mm², less than 10 attachments/mm², less than 9attachments/mm², less than 8 attachments/mm², less than 7attachments/mm², less than 6 attachments/mm², less than 5attachments/mm², etc.).

When the second layer (e.g., the adhesion barrier/anti-adhesivematerial) is sewn or embroidered onto the substrate (e.g., mesh, or meshplus first embroidered pattern), the second layer may comprises one ormore sheets of adhesion barrier material, such as ECM. As mentioned,after attachment with the stitching pattern described herein, the one ormore sheets may be movable relative to the substrate. For example, theone or more sheets may be joined to the substrate with a stitch patterncomprising at least one filament, thread, or yarn. The stitchingmaterial (e.g., filament, thread, etc.) may be formed of any appropriatematerial, including a polymeric material. The stitching material may beformed of the same material as the adhesion barrier sheets.

The attachment stitch pattern securing the substrate mesh to theanti-adhesive material may comprise a plurality of stitch islands,whereby the at least one filament, yarn, or thread are sewn at discreetlocations about the substrate, with regions that are unattached (e.g.,having no stitch pattern, filament, yarn, or thread) in between stitchislands. The stitched attachment pattern may comprise a plurality ofstraight lines oriented along one or more axes of the substrate. Asubset of straight lines oriented along different axes of the substratemay intersect, and may form a grid pattern. The stitched attachmentpattern may comprise a plurality of parallel lines. The stitch patternmay comprise a plurality of lines arranged in a zig-zag. A subset of thelines in a zig-zag may comprise a different amplitude, frequency, oramplitude and frequency relative to another subset of the lines in azig-zag in the stitch pattern. The stitched attachment pattern maycomprise a plurality of lines arranged in a pattern comprising aplurality of curves, including a wave pattern (e.g., a sinusoidal wave)or an oscillating line pattern. A subset of the lines in a curve patternmay comprise a different amplitude, frequency, or amplitude andfrequency relative to another subset of the lines in a curve in thestitch pattern. The stitched attachment pattern may be random. Thestitched attachment pattern may be continuous or comprise breaks orinterruptions. The stitched attachment pattern may comprise acorner-lock stitch pattern. The stitched attachment pattern may comprisean upper filament, thread, or yarn and a lower filament, thread, oryarn. The upper filament, thread, or yarn may comprise a larger diameterrelative to the lower filament, thread, or yarn, or may comprisesubstantially the same diameter relative to the lower filament, thread,or yarn, or may comprise a smaller diameter relative to the lowerfilament, thread, or yarn. The upper filament, thread, or yarn and thelower filament, thread, or yarn may comprise any one or more ofchitosan, hyaluronic acid, icodextrin, fibrin,poly(L-lactide-co-D,L-lactide)/polylactic acid, polytetrafluoroethylene,or oxidized regenerated cellulose, including any combination thereof.The one or more adhesion barrier sheets may comprise any one or more ofchitosan, hyaluronic acid, icodextrin, fibrin,poly(L-lactide-co-D,L-lactide)/polylactic acid, polytetrafluoroethylene,or oxidized regenerated cellulose, including any combination thereof.

Methods for making any of the implants (e.g., grafts) or substratematerials are also described herein. Methods may comprise, for example,sewing or embroidering an adhesion barrier material into one or morestitched attachment patterns to secure the anti-adhesive material(sheet, e.g., ECM) to any of the substrate materials (e.g., meshes)described or exemplified herein. In some aspects, such methods comprise,for example, sewing one or more sheets comprising an adhesion barriermaterial onto any substrate material described or exemplified herein.The substrate may first have a first pattern of embroidered onto it(e.g., compliance limiting pattern) in a material having a greaterbioabsorbability than the substrate material. For example the mesh maybe relatively highly compliant but may have a compliance-limitingstitching pattern embroidered onto it with a lower compliance material;this mesh with an embroidered material may then be stitched in a second(attachment) pattern of discrete attachment sites (e.g., stitches).

Any of the apparatuses (e.g., grafts) described herein may be used torepair tissue. For example, described herein are methods for inhibitingadhesions while repairing or reconstructing tissue in a subject in needthereof. Such methods may generally comprise implanting an implant orsubstrate material comprising an adhesion barrier sewn or embroideredinto the implant or substrate or comprising one or more adhesion barrierlayers sewn onto the implant or substrate at a location in the body ofthe subject in need of tissue repair or tissue reconstruction. Thetissue may be any tissue in the body, including soft tissue. The tissuemay comprise a hernia, such that the implant or substrate is used torepair the herniation. Once implanted, the adhesion barrier inhibitsadhesions between tissue in the body and the implant or substrate, andmay also further inhibit adhesions between adjacent tissues in the bodythat is proximal to the implant. The subject may be human being or otheranimal (e.g., veterinary animal, non-human animal, etc.).

For example, described herein are hernia repair grafts. A hernia repairgraft may include: a first layer comprising a mesh; a second layercomprising a sheet of anti-adhesive material, wherein the second layeris flexibly attached to the first layer with a pattern of discreteattachment sites, wherein the pattern of discrete attachment sitesalters the compliance of the stacked first and second layers by lessthan 15% and adjacent regions of the first layer and second layerbetween the discrete attachment sites may slide relative to each other.

A hernia repair graft may include: a first layer comprising a knitted,non-bioabsorbable mesh and a first pattern embroidered into the meshwith a bioabsorbable material; a second layer comprising a sheet ofanti-adhesive material attached at discrete attachment sites along thefirst layer such that adjacent discrete attachment sites are separatedby a distance of between 0.5 mm and 30 mm, and adjacent regions of thefirst layer and the second layer between the discrete attachment sitesmay slide relative to each other.

Any of the hernia repair grafts described herein may include: a firstlayer stacked onto a second layer; wherein the first layer comprises: amesh formed of a non-absorbable material and a first pattern stitchedinto the mesh with a bioabsorbable material; wherein the second layercomprises an anti-adhesive material comprising a plurality of sheets ofextracellular matrix material (ECM); further wherein the second layer isflexibly attached to the first layer with a second pattern of discretestitched attachment sites, wherein the second pattern of discretestitched attachment sites is less dense than the first pattern stitchedinto the mesh, wherein adjacent discrete attachment sites are separatedby a distance of between 0.5 mm and 30 mm and wherein adjacent regionsof the first layer and second layer between the discrete attachmentsites may slide relative to each other.

In any of the grafts described herein, the second pattern (e.g., theattachment pattern) may be a second stitching pattern of discreteattachment sites. The second pattern may be less dense than the firstpattern in the plane of the first layer.

In general the substrate may be a mesh. The mesh may be a knitted mesh,a woven mesh, or a formed mesh. The mesh may be formed of polypropylene,polytetrafluoroethylene (PTFE), nylon, polyester, or the like (includingcombinations of these). The mesh may have an open cell pore diameter ofbetween 0.5 mm and 6 mm (e.g., 0.0197 inches and 0.24 inches). The meshmay be formed of a warp knitted filament having a diameter of between0.001 inch and 0.010 inches. For example, the mesh may be formed of awarp knitted filament having a diameter of between 0.003 inch and 0.006inches. The mesh may be formed of a plurality of fibers that are knittedtogether (multi-filament) or a monofilament. In some variationsmulti-filament fibers (for either or both the mesh and the sewnmaterials) may be preferred because they may be stronger.

As mentioned above, the first pattern (e.g., the pattern embroideredinto the mesh) may comprise adjacent lines of stitching that cross tointerlock at regular intervals. The first pattern may comprise a firststitching sub-pattern and a second stitching sub-pattern, wherein thefirst stitching sub-pattern overlaps with the second stitchingsub-pattern and the first stitching sub-pattern is rotated between 25and 65 degrees relative to the second stitching sub-pattern.

The anti-adhesive material may comprise extracellular matrix (ECM), suchas ECM derived from one or more of the dermis, pericardium, peritoneum,intestine, stomach, or forestomach. The second layer may comprise aplurality of stacked sheets of the extracellular matrix (ECM) material.

As mentioned, the discrete attachment sites may comprise a secondstitching pattern, such as a grid pattern. The adjacent discreteattachment sites may be separated by a minimum distance or a range ofdistanced (e.g., between 0.5 mm and 30 mm). The second layer may beflexibly attached to the first layer with a second pattern of discreteattachment sites having a density of attachment sites that is less than,e.g., about 10 attachments/mm².

In general, in any of these materials (e.g., hernia repair grafts) thecompliance strain of the material may be between 10-30% at 16 N/cm. Thisrange of compliance may be particularly well suited to match thecompliance of the tissue that the hernia is repairing, to preventdiscomfort and potential re-injury of the repair site. Within thisrange, at least when initially implanted, the material may result in farsuperior medical outcomes; outside of this range the implant may be lesscomfortable and may require further future treatment. It has also befound to be advantageous to have the compliance of the hernia repairgraft increase over time, as the surrounding tissues heals and grows(e.g., into the implant). As mentioned above, the embroidered firstpattern may decreases the compliance of the the mesh so that thecompliance of the hernia repair apparatus will increase over time in apatient as the bioabsorbable material is absorbed. The attachment sitesattaching the second layer to the first layer may form a grid pattern ofcells each having a diameter, e.g., of between 10 mm and 35 mm.

A hernia repair graft may include: a first layer stacked onto a secondlayer; wherein the first layer comprises: a mesh formed of anon-absorbable material and a first pattern embroidered into the meshwith a bioabsorbable material; wherein the second layer comprises asheet of anti-adhesive material comprising an extracellular matrix (ECM)material; further wherein the second layer is flexibly attached to thefirst layer with a second pattern of discrete attachment sites, whereinthe second pattern of discrete attachment sites alters the compliance ofthe stacked first and second layers by less than 15% and adjacentregions of the first layer and second layer between the discreteattachment sites may slide relative to each other.

A hernia repair graft may include: a first layer stacked onto a secondlayer; wherein the first layer comprises: a mesh formed of anon-absorbable material and a first pattern stitched into the mesh witha bioabsorbable material; wherein the second layer comprises ananti-adhesive material comprising a plurality of sheets of extracellularmatrix material (ECM); further wherein the second layer is flexiblyattached to the first layer with a second pattern of discrete stitchedattachment sites, wherein the second pattern of discrete stitchedattachment sites is less dense than the first pattern stitched into themesh, and wherein adjacent regions of the first layer and second layerbetween the discrete attachment sites may slide relative to each other.

A hernia repair graft may include: a first layer stacked onto a secondlayer; wherein the first layer comprises: a mesh formed of anon-absorbable material and a first pattern stitched into the mesh witha bioabsorbable material, wherein the first pattern decreases thecompliance of the the mesh so that the compliance of the hernia repairapparatus will increase over time in a patient as the bioabsorbablematerial is absorbed; wherein the second layer comprises ananti-adhesive material comprising a sheet of extracellular matrixmaterial (ECM); further wherein the second layer is flexibly attached tothe first layer with a second pattern of discrete stitched attachmentsites, wherein adjacent discrete attachment sites are separated by adistance of between 0.5 mm and 30 mm and wherein the second pattern ofdiscrete stitched attachment sites is less dense than the first patternstitched into the mesh, and further wherein adjacent regions of thefirst layer and second layer between the discrete attachment sites mayslide relative to each other.

As mentioned above, also described herein are methods for repairing ahernia in a subject. These methods may include implanting any of thehernia repair grafts described herein into the body of the subject at alocation within the body in need of hernia repair or reconstruction,thereby repairing or reconstructing the hernia and inhibiting theformation of adhesions between the body and the implant.

Also described herein are methods of making a hernia repair graft. Forexample a method of making a hernia repair graft may include:embroidering a first pattern into a non-absorbable mesh using abioabsorbable material, wherein the first pattern decreases thecompliance of the mesh; attaching a sheet of an anti-adhesive materialcomprising a sheet of extracellular matrix material (ECM) to the mesh ata plurality of discrete attachment sites, wherein the discreteattachment sites are separated by a distance of between 0.5 mm and 30 mmand wherein the second pattern of discrete stitched attachment sites isless dense than the first pattern stitched into the mesh, and furtherwherein adjacent regions of the mesh and sheet of anti-adhesive materialbetween the discrete attachment sites may slide relative to each other.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe claims that follow. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings. The various features of the drawing are not toscale. On the contrary, the dimensions of the various features arearbitrarily expanded or reduced for clarity.

FIG. 1 shows an example of an adhesion barrier (e.g., ECM) to a meshsubstrate using a grid of island-based embroidery stitches. In the firstpanel, the barrier (center), mesh substrate (bottom), and islandstitches (top) are shown in an exploded view. In the second panel, thebarrier has been placed atop of the mesh substrate, with the islandstitches not yet applied. In the third panel, the stitch pattern hasbeen embroidered into the barrier and mesh substrate layers, joiningthem into a substrate-barrier unit.

FIGS. 2A through 2G show different stitch patterns for the discreteattachment sites (stitches) that may be used to join an adhesion barrierto a mesh substrate to form a substrate-barrier unit. FIG. 2A shows anisland stitch pattern, with the stitches forming small islands. FIG. 2Bshows an island stitch pattern, with the stitches forming largerislands. FIG. 2C shows a grid stitch pattern. FIG. 2D shows a zig-zagstitch pattern. FIG. 2E shows a curve stitch pattern. FIG. 2F shows aninterrupted stitch pattern. FIG. 2G shows a random stitch pattern.

FIG. 3 shows an example of a first pattern embroidered onto a meshsubstrate. In FIG. 3, the embroidering threads may be made of anyappropriate material, including an adhesion barrier material, and aresewn (embroidered) into the mesh substrate. In the first two panels, themesh substrate is on the bottom with the stitch pattern (threads sewn asa zig-zag pattern in this example) above them in the exploded view. Inthe third panel, the stitch pattern is shown sewn into the meshsubstrate.

FIG. 4A shows a side view of threads (e.g., which may be made of anadhesion barrier material) sewn into a substrate; the lockstitch of theupper and lower threads is shown (dotted lines). The upper thread has alarger diameter relative to the lower thread in this example. FIG. 4Bshows an isometric perspective view of the embroidered substrate shownin FIG. 4A.

FIG. 5A shows a representation of a substrate mesh without anyembroidered pattern. FIG. 5B shows a close-up view of the substrate fromFIG. 5A into which threads (e.g., of an adhesion barrier material) havebeen sewn. The upper thread has a larger diameter relative to the lowerthread. FIG. 5C shows a side view of the threads sewn into thesubstrate. FIG. 5D shows a representation of the substrate fabric ormesh into which a high density of threads have been sewn. FIG. 5E showsa top perspective view of FIG. 5D.

FIG. 6A shows a representation of a substrate fabric or mesh into whichthreads (e.g., of an adhesion barrier material) have been sewn. Theupper thread has a larger diameter relative to the lower thread. FIG. 6Bshows a side view of the threads sewn into the substrate. FIG. 6C showsa representation of the substrate fabric or mesh into which a highdensity of threads have been sewn.

FIG. 7A shows a representation of a substrate material into whichcrisscrossing threads have been embroidered. In each pass of theembroidered threads, the upper thread has a larger diameter than thelower thread. FIG. 7B shows a representation of the substrate fabric ormesh into which a high density of crisscrossing threads have been sewn.

FIGS. 8A through 8G show different stitch patterns that may be used toembroider a mesh substrate. FIG. 8A shows an example of a grid patternof threads sewn into the mesh substrate. FIG. 8B shows an example of azig-zag pattern of threads sewn into the mesh substrate. FIG. 8C showsan example of a higher density (relative to the pattern shown in FIG.8B) zig-zag pattern of threads sewn into the mesh substrate, with thethreads having a larger diameter (relative to the pattern shown in FIG.8B). FIG. 8D shows an example of a zig-zag pattern of barrier threadssewn into the mesh substrate, with the zig-zag pattern having differentamplitude and frequency (relative to the pattern shown in FIG. 8B). FIG.8E shows an example of a curved pattern of threads sewn into the meshsubstrate. FIG. 8F shows an example of an interrupted pattern of threadssewn into the mesh substrate. FIG. 8G shows an example of a randompattern of threads sewn into the mesh substrate.

FIGS. 9A through 9D show an enlarged view of portions of the stitchpatterns shown in FIGS. 8A through 8D. The expanded views show that thethreads interlace about the mesh substrate.

FIG. 10A shows a side view of threads (e.g., which may be made of anadhesion barrier material) sewn through both a substrate (e.g., mesh)and an adhesion barrier (e.g., ECM). In this example, the threads areshown passing through both layers forming a series of discreteattachment sites connecting the adhesion barrier and the substrate. Aline of discrete attachment sites is formed. In this example, theadhesion barrier layer comprises two ECM layers. The adhesion stitchingpattern shown comprises a lockstitch of an upper and lower thread. Inthis example, the upper thread has a larger diameter relative to thelower thread. FIG. 10B shows an isometric perspective view of FIG. 10A.

FIG. 11A shows an exploded view of a hernia repair graft including asubstrate first layer and an adhesion barrier second layer formed of aplurality (two sheets, in this example) of sheets of ECM. FIG. 11B showsa view of a first side of the graft (mesh side), showing the layersstacked and attached in a pattern of discrete stitched attachment sites,formed by stitching in this example. In FIG. 11C the opposite side ofthe graft (ECM side) is shown.

FIG. 12A shows an exploded view of a hernia repair graft including anembroidered substrate first layer and an adhesion barrier second layerformed of a plurality (two sheets, in this example) of sheets of ECM.FIG. 12B shows a view of a first side of the graft (embroidered meshside), showing the layers stacked and attached in a pattern of discretestitched attachment sites, formed by stitching. In FIG. 12C the oppositeside of the graft (ECM side) is shown, showing the attachment stitchingpattern is less dense than the stitching pattern embroidered on themesh. In any of the grafts herein, an additional adhesion barrier may beattached over the first side as well.

FIG. 13A shows an example of a mesh (substrate) of a hernia repairgraft, having an open-cell configuration. This mesh is formed ofpolypropylene. FIG. 13B shows the mesh of FIG. 13A embroidered in a pairof grid sub-patterns with a bioabsorbable material.

FIG. 14A shows the first side of a hernia repair graft including a mesh,such as the mesh shown in FIGS. 13A-13B, to which an anti-adhesivematerial (in this example, sheets of ECM) has been sewn. FIG. 14B showsthe back side of the hernia repair graft, showing the anti-adhesivematerial and a stitching pattern attaching the mesh to the anti-adhesivematerial. This stitching pattern comprises a plurality of discreteattachment sites arranged in the rectangular grid (25 mm×25 mm).

FIG. 15A is a graph showing the percent change in mesh compliance of anunconnected stack of a first embroidered mesh layer and a second ECMlayer, under attachment conditions, including gluing the two layerstogether, gluing with low-density spots (e.g., spots approximately0.01-0.001 inches separated by an average of approximately 5-20 mm),stitching in low density (e.g., stitches of 0.010 thread separated by anaverage of 5-20 mm), stitching at high density (e.g., stitches of 0.010thread separated by an average of 1-5 mm).

FIG. 15B is a qualitative graph illustrating the change in likelihood offorming adhesions when implanted in the body based on the attachmentsite density when using a rectangular stitching pattern of 25 to 1 mmL×V. This curve shows the generally increasing trend from low to higherprobability of forming an adhesion as the density of the attachmentsites (e.g., stitches). In this example, the anti-adhesive materialcomprises 2 layers of ECM.

FIGS. 15C and 15D are qualitative graphs illustrating the compliance ofthe grafts described herein based on their stitch density in which thestitching pattern has a closed cell pattern (FIG. 15C) and an open-cellpattern (FIG. 15D). In general, the less adhesion material (e.g., stitchmaterial or glue material, such as polymer) per unit area between themesh and the anti-adhesion layers the greater the compliance, althoughit may reduce the tensile strength. Both figures illustrate that (forlayered sheets of anti-adhesion material, e.g., 2, 3, or 4 sheetlayers), the compliance decreases as the stitch density increases.

FIG. 16 is a qualitative bar graph showing the percent compliance strainat 16 N/cm for meshes, including those described herein, the same mesheswhen embroidered, e.g., with a bioabsorbable material, embroideredmeshes stitched to ECM as described herein, and embroidered meshes theECM laminated.

DETAILED DESCRIPTION

Described herein are apparatuses (e.g., devices, systems, materials,including but not limited to grafts, such as hernia repair grafts),methods for repairing soft tissue using such apparatuses and methods ofmaking these apparatuses. These apparatuses may have desirablebiomechanical and biochemical properties, including having a compliancethat matches the body, and that changes over time in the body asportions are controllably absorbed in a manner that promotes healing andstrengthen of the resulting tissue. Further, these apparatuses mayinclude an anti-adhesion (e.g., “adhesion barrier”) barrier on one orboth sides of the relatively flat material (e.g., graft).

In general, these apparatuses may include a first layer and a secondlayer that are flexibly attached through a plurality small and discreteattachment sites distributed between the layers. The first layer, orsubstrate, may include a mesh. The mesh may be reinforced with one ormore filaments embroidered in a first pattern. The mesh may have a firstcompliance and the compliance of the mesh may be decreased whenreinforced with the embroidered pattern. The second layer generallyincludes an anti-adhesion layer, which may comprise one or more sheetsof material, such as a biologic (e.g., ECM) the like.

As described in greater detail below, an apparatus may include a firstlayer comprising a mesh and a second layer comprising a sheet ofanti-adhesive material. Examples of the first layer are provided herein,including examples having an embroidered pattern. The second layer mayinclude one or more sheets of anti-adhesive material stacked atop eachother. The first layer may be attached to the second layer with aplurality of relatively small attachment sites that are separated byregions in which the two layers are not attached. The sizes of thediscrete attachment sites, the spacing between discrete attachmentsites, and/or the density (e.g., average density) and/or pattern(s) ofattachment sites may be controlled so that attachment of the two layersdoes not change the relative compliance of the first and/or secondlayer. Specifically, the attachment sites may change the overallcompliance of the material (e.g., graft) 15% or less (e.g., 13% or less,10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less,etc.) compared to the compliance of either the first layer, the secondlayer, or a stack of the first and second layer that are not connectedtogether. The flexible attachment between these two layers may refer tothe ability of the regions of the first and second layer between thediscrete attachment sites to slide relative to each other.

The discrete attachment sites may be stitches and/or chemical adhesives(e.g., glues). The discrete attachment sites may be separated from oneanother (or from adjacent groups of one another) by a distance ofbetween 0.5 mm and 30 mm. The discrete attachment sites may have adiameter of between about 0.001 inch and 0.20 inches (e.g., betweenabout 0.001 inches to about 0.010 inches, between about 0.001 to about0.060 inches, etc.). The discrete attachment sites may be individualattachment sites (e.g., threads passing through the layers) or smallgroups of attachment sites (e.g., a plurality of threads that intersectand/or interlock as they pass through the material).

Adhesion barriers may be sewn onto or sewn into surgical implants suchas a biotextile or medical textile (e.g., a hernia repair scaffold). Thecombination of the substrate or scaffold (e.g., mesh) and the adhesionbarrier (e.g., sheet or sheets of ECM) may inhibit adhesions between theimplanted scaffold and other tissues in the body. The adhesion barrierfurther imparts additional benefits into the scaffold, includingstrength and axial stiffness, as well as benefits to the implantationprocedure such as placement orientation and additional suturing points.In addition to adhesion inhibition, the scaffold-adhesion barriercombination provides additional benefits to the patient as it lessensthe need to implant a secondary adhesion barrier or to apply ananti-adhesion material at the surgical site, thereby lessening thepotential for an infection or other complication.

Biotextile or medical textile scaffolds such as meshes may be used forsoft tissue repair or reconstruction and, in this capacity, maygenerally be surgically implanted within the body. Such scaffolds mayserve, for example, to replace or reinforce diseased or damaged softtissue, or to hold internal organs in place in the case of a herniarepair. In some cases, these scaffolds are intended to be a permanentfixture within the body. In other cases, these scaffolds are intended tobe a temporary fixture within the body such that they are made of amaterial that is gradually resorbed by the body as it is replaced by thebody's own tissue.

The substrate material may be any material onto or into which anadhesion barrier may be sewn according to this disclosure (“substrate,”“scaffold,” and “substrate material” and “substrate materials” are usedinterchangeably herein). A substrate material may be a natural orsynthetic material, may be a textile, and may be knitted, braided, wovenor non-woven. Typical substrate materials may preferably include, butare not limited to, meshes. The substrate material may have anythickness, or length and width dimensions. The substrate material may bea biotextile or a medical textile. Biotextiles or medical textiles maybe implantable in or on the human body. Thus, a substrate or substratematerial may be an implant or a part of an implant.

Although the substrate may preferably be non-absorbable (e.g., having avery low bioabsorbability). Biotextiles include biocompatible materials,which may also include bioabsorbable materials. Biotextiles may besynthetic or may be obtained or derived from living tissue. Livingtissue includes, for example dermis/skin tissue (and sub-tissue,extracellular matrices), pericardium, peritoneum, amnion, intestine,stomach, forestomach, and other suitable tissues. The animal source maybe any suitable animal, including a mammal such as human, pig, cow, orsheep, or may be synthesized, for example, by recombinant expression.Biotextiles may be biodegradable or resorbable. Biotextiles may comprisecollagen, or reconstituted collagen. Some non-limiting examples ofbiotextiles include extracellular matrix-derived tissue scaffolds orpatches, autograft tissue, allograft tissue, and xenograft tissue, aswell as artificial skin, artificial heart valves, and other implantableprosthetics. Medical textiles include biocompatible materials, which mayinclude synthetic materials. Some non-limiting examples of medicaltextiles include hernia repair patches or meshes.

As mentioned both the scaffold and the anti-adhesive layers may bemedical textiles and/or may comprise a biodegradable or resorbablematerial or a non-absorbable material. The medical textile material maycomprise a polydioxanone, polycarbonate, polyurethane,poly(alpha-ester), polyglycolide, polylactide (e.g., poly(L-lacticacid), poly(D-lactic acid), and poly(D,L-lactic acid), poly(4-hydroxybutyric acid)—which is a homopolymer of 4-hydroxybutyrate(4HB), and belongs to a diverse class of materials calledpolyhydroxyalkanoates (PHAs)—and poly(lactide-co-glycolide)),polycaprolactone, polypropylene, polyester, poly(propylene fumarate),polyanhhydride, polyacetal, polycarbonate (e.g., poly(trimethylenecarbonate)), poly(ortho ester), polyphosphazene, polyphosphoester,polytetrafluoroethylene, polyethylene terephthalate, or any combinationor co-polymer thereof. Polypropylene, polyester, and polyethylene are apreferred medical textile materials. Co-polymers or mixtures of suchpolymers may also be used, for example, as a way to modulate theproperties of the medical textile, including to make the medical textilemore or less capable of stretching, or more or less stiff, or strongeror weaker, or for long-term, mid-term, or short-term potential forresorption/biodegradation.

The substrate material may comprise any suitable thickness, size, ordimensions. These properties may relate, in part, to the intendedlocation of the substrate material once implanted in the body, as wellas particular patient needs, condition, or characteristics. In someaspects, the substrate comprises a single layer. In some aspects, thesubstrate comprises a plurality of layers. The substrate may be threedimensional. In embodiments where the substrate is sewn (embroidered),one or more or the layers in a substrate comprising a plurality oflayers may be sewn together in a first pattern.

The substrate material may comprise a film, preferably a biocompatiblefilm. The film may comprise a layer placed on the outer surfaces of thesubstrate material, or the film may constitute the entire substratematerial. The substrate material may comprise a coating or otherwise beimpregnated with one or more therapeutic agents. For example, thesubstrate material may comprise an antibiotic or anti-inflammatorytherapeutic agent.

The adhesion barrier is preferably incorporated as a layer onto thesubstrate material. The adhesion barrier may comprise a separate sheet,leaf, or layer that is sewn onto the substrate material or sewn into alayer of substrate material where the implant comprises more than onelayer of substrate material. When the discrete attachment sites arestitches, these these stitches may be sewn using a material that is alsoanti-adhesive.

The adhesion barrier may comprise any material that is suitable forimplantation within a patient that has anti-adhesion properties orfunctionality. The adhesion barrier/anti-adhesion material may comprisechitosan, collagen, hyaluronic acid, icodextrin, fibrin,poly(L-lactide-co-D,L-lactide)/polylactic acid, polydioxanone,polytetrafluoroethylene, oxidized regenerated cellulose (ORC), ahydrogel, or any combination thereof. ORC is preferred. A hydrogel maycomprise a self-healing hydrogel scaffold. The adhesionbarrier/anti-adhesion material may be in the form of a scaffold, mesh,film, sheet, leaf, membrane, filament, thread, yarn, or other formsuitable for inclusion as a layer that is sewn/embroidered onto orsewn/embroidered into a substrate material.

The adhesion barrier material may be resorbable by the body. In someaspects, the adhesion barrier material is substantially resorbed by thehuman body by about three weeks following implantation of the implantwithin the human body. In some aspects, the adhesion barrier material issubstantially resorbed by the human body by about one month followingimplantation of the implant within the human body. In some aspects, theadhesion barrier material is substantially resorbed by the human body byabout six weeks following implantation of the implant within the humanbody. In some aspects, the adhesion barrier material is substantiallyresorbed by the human body by about two months following implantation ofthe implant within the human body. In some aspects, the adhesion barriermaterial is substantially resorbed by the human body by about six monthsfollowing implantation of the implant within the human body. In somevariations the adhesion barrier (anti-adhesive material) is not absorbedby the body.

An adhesion barrier in the form of a mesh, sheet, leaf or membrane mayhave any suitable dimensions (e.g., 1×w), and may have any suitablethickness. A plurality of sheets may be used (which sheets may, but neednot be, joined together, for example, with an adhesive or by sewingsheets together, or may be unjoined until they are all attached to thesubstrate) in order to enhance the thickness and/or the duration ofadhesion inhibition within the body. An adhesion barrier may be colored.Colors may be used to indicate a proper orientation of the substrate forimplantation, for example, or may indicate a front or back.

A filament, yarn or thread that is used sew an adhesive barrier onto asubstrate may comprise any suitable material, including any adhesionbarrier material described or exemplified herein. The filament, yarn, orthread, whether or not it comprises an adhesion barrier material, maycomprises a non-bioabsorbable or a biodegradable/bioresorbable material,including any such material suitable for use as a medical textile asdescribed or exemplified herein. Preferred materials may include,without limitation, ORC, polyglycolic acid, polylactic acid,polydioxanone, or any combination thereof.

A filament, yarn or thread used to stitch/embroider an adhesive barrier(anti-adhesive material) into or onto a substrate may comprise anysuitable weight. The yarn or thread may comprise monofilament yarn orthread, or multi-filament yarn or thread. The thread weight may rangefrom about 20 weight to about 120 weight. The thread may comprise adenier of from about 1 denier to about 2000 denier. The thread maycomprise a denier of at least about 20-denier. The thread may comprise adenier of at least about 30-denier. The thread may comprise a denier ofat least about 40-denier. The thread may comprise a denier of at leastabout 50-denier. The thread may comprise a denier of at least about60-denier. The thread may comprise a denier of at least about 70-denier.The thread may comprise a denier of at least about 80-denier. The threadmay comprise a denier of at least about 90-denier. The thread maycomprise a denier of at least about 100-denier. The thread may comprisea denier of at least about 120-denier. The thread may comprise a denierof at least about 150-denier. The thread may comprise a denier of atleast about 200-denier. The thread may comprise a denier of at leastabout 250-denier. The thread may comprise a denier of at least about300-denier. The thread may comprise a denier of at least about400-denier. The thread may comprise a denier of at least about500-denier. The thread may comprise a denier of at least about600-denier. The thread may comprise a denier of at least about700-denier.

For example a yarn of an anti-adhesion material may be used and maycomprise plied yarn or twisted yarn (e.g., z twist or s twist), or maycomprise a braided yarn. The thread of an anti-adhesion material maycomprise a continuous filament. The thread of an anti-adhesion materialmay comprise a staple filament. The filament, yarn or thread may becolored. Colors may be used to indicate a proper orientation of thesubstrate for implantation, for example, or may indicate a front orback.

The combination of a substrate and adhesion barrier, whether the barrieris sewn onto or sewn into the substrate (e.g., the substrate-barrierunit), may be used in a surgical implantation procedure, for example,for purposes of soft tissue repair or regeneration such as a herniarepair. Once the substrate-barrier unit is implanted within thepatient's body, the adhesion barrier serves to inhibit adhesionformation, at least between the substrate and adjacent tissue or organsin the body.

An adhesion barrier layer (e.g., sheet) may be sewn onto the substrate,forming a plurality of discrete attachment sites corresponding to thestitches between the two layers. The adhesion barrier layer may besufficiently flexible (compliant) so as not to stiffen the substratematerial or restrict the intended and natural flexibility of thesubstrate within the body, less the substrate-barrier unit causediscomfort within the patient. The stitching pattern that joins theadhesion barrier layer to the substrate material can be selected toallow the adhesion barrier layer to move and flex with the movement andflexing of the substrate, particularly when implanted. Relative movementamong layers of the substrate-barrier unit permits bending andpliability of the substrate-barrier unit, for example, in order tocompensate for any reduction in flexibility caused by multiple layersincreasing the thickness of the substrate-barrier unit. For example, thestitching type, stitching pattern, stitching density, and stitchinglocation(s), as well as the stitch density and number of stitches maymodulate flexibility and capacity for movement, as well as provide for amore stable attachment between the adhesion barrier layer and thesubstrate. The filament, thread, or yarn preferably comprises anadhesion barrier material such as ORC. Where the discrete attachmentsites are formed by an adhesive rather than or in addition to a stitch,the same considerations list above for stitching may apply (e.g.,attachment pattern, attachment density, attachment location(s), etc.).

The adhesion barrier layer (e.g., sheet) may be joined to the substratematerial in a way that the adhesion barrier layer is more freely movable(e.g., slideable) or flexible relative to the substrate material, and/orrelative to the different layers of a substrate material where thesubstrate material comprises a plurality of layers. The capacity of theadhesion barrier to move may relate to the stitching pattern, as well asaspects of stitching such as the density or number of stitches, anglesof the stitch pattern, stitch direction, and the overlay of one or morestitch patterns, as well as the placement and relative tightness orlooseness of how the stitches are laid.

After the adhesion barrier layer and substrate material are joinedtogether, it may be necessary or desired to trim or cut thesubstrate-barrier unit, for example, in order to reduce its size or toconform to a desired shape. For example, such size or shape adjustmentsmay be to accommodate the needs or situation of the patient into whichthe substrate-barrier unit is implanted. Thus, it is highly preferredthat the stitching pattern used to join the adhesion barrier layer andthe substrate together is laid in a way (e.g., at a sufficient density(e.g., relatively high density sewing), number of thread interlacepoints, etc.) that allows the remaining substrate-barrier unit to remainjoined together without delaminating, or without having loose severedends of threads hanging off of the cut points on the substrate-barrierunit.

The stitching pattern to join an adhesion barrier (e.g., sheet(s)) tothe substrate material may constitute a single stitch pattern or acombination of stitch patterns. The type of stitch may include a chainstitch, Merrow stitch, lock stitch, zigzag stitch, straight stitch,running stitch, back stitch, satin stitch, or combinations thereof. Anyof these stitching types or patterns may be used to form the embroideredpattern on the substrate as well.

The stitching pattern to join an adhesion barrier (e.g., sheet) to thesubstrate material may comprise one or more straight lines. Thestitching pattern to join an adhesion barrier (e.g., sheet) 20 to thesubstrate material 10 may comprise island stitches 30, whereby stitchesare laid at certain points in the substrate and the adhesion barriersheet (the islands), with spaces in between having no stitching (FIG. 1,FIG. 2A, and FIG. 2B). FIG. 2A shows an example of a small island stitchpattern 30 and FIG. 2B shows an example of a large island stitch pattern30. Where a plurality of straight lines are employed, they may besewn/embroidered in parallel, including in a grid pattern 30 (FIG. 2C),or they may be sewn/embroidered or in a straight or a zig-zagconfiguration 30 (FIG. 2D), or they may be sewn/embroidered in aconfiguration comprising a plurality of curves such as waves,oscillating lines, ripples, undulations, and other forms of curves (FIG.2E). The stitching pattern may also comprise interrupted patterns (e.g.,interrupted straight lines, interrupted curves, interrupted zig-zags,and interruptions of other patterns described or exemplified herein, orotherwise known), with a non-limiting example of an interrupted zig-zagshown in FIG. 2F. The stitching pattern may also comprise randompatterns, a non-limiting example of which is shown in FIG. 2G.

In any of the apparatuses described herein (including the grafts, etc.)a reinforcing embroidered pattern may be sewn into the substratematerial. See, for example, FIG. 3. In this example, threads or yarns 50(which may be an adhesion barrier material) may be are sewn orembroidered into the substrate material 10. The embroidered threads(fibers, etc.) may form a layer that is integral with the substratematerial (FIG. 3, third panel), and connected to the substrate materialat numerous thread interlace points (e.g., FIG. 4A) established wherethe sewing needle punctures the substrate material and the threads oryarns are intertwined together by the coordination of the sewing needle(for an upper thread/yarn) and bobbin/bobbin driver (for a lowerthread/yarn). Each stitch may comprise one or more, e.g., at least twothreads, yarns, or filaments—e.g., an upper thread and a lower thread,which each are sewn into the substrate material. In some variation,where the embroidered pattern is sufficiently dense, an additionalanti-adhesion layer is not needed; however, in general, an adhesionbarrier is preferably attached (flexibly attached) to the substratematerial. Sewing or embroidery may be by hand, by machine, or anycombination thereof. Sewing may be with a ballpoint needle.

As mentioned, the addition of the embroidered pattern of material (e.g.,typically a bioabsorbable material or a material having a greaterbio-absorption than the substrate/mesh) may decrease the compliance ofthe substrate. In the apparatuses described herein it has been found tobe of particular medical benefit to use a substrate (e.g., mesh) havinga compliance that is greater than the range of compliances identified asmost beneficial for soft tissue (e.g., hernia) repair, such as the rangeof between 10% and 30% compliance strain at 16N/cm (see, e.g., Deeken etal. (2011), Physiocomechanical evaluation of absorbable andnonabsorbable barrier composite meshes for laparoscopic ventral herniarepair. Surg. Endosc., 25(5), 1541-1552). For example, the bare mesh mayhave a % compliance strain at 16N/cm of between 30% and 80%). Theaddition of the embroidered pattern, typically using a filament that isbioabsorbable in a pattern such as a grid pattern (or a plurality ofoverlapping, rotationally offset, grid patterns) may decrease the %compliance strain at 16N/cm to within the 10%-30% range or thereabouts(e.g., between 40%-10%).

Filaments, threads, or yarns may be sewn in both the embroidered patternon the mesh and/or the pattern connecting the substrate to theanti-adhesion layers may be any suitable stitch patterns. In someaspects, the material is sewn as a line, for example, as shown in FIG.4A and FIG. 4B. For example, using a sewing machine, an upper thread 32and lower thread 34 of adhesion barrier material may be sewn into thesubstrate 10. The upper thread 32 may have a larger diameter relative tothe lower thread 34 (FIG. 4A), though the upper 32 and lower 34 threadsmay have substantially the same diameter relative to each other, or thelower thread 34 may have a larger diameter relative to the upper thread32. The upper thread 32 and lower thread 34 may be joined at a threadinterlace point 36, created by the sewing machine. A suitable diametermay be from about 0.001 inches (about 0.0025 mm) to about 0.05 inches(about 1.27 mm) for a monofilament or multifilament.

The adhesion barrier materials may be attached to the substrate in asewn pattern that is different from that of the embroidered pattern(which is typically a tighter, higher-density pattern). The embroideredpattern may be a pattern comprising a plurality of lines, includingparallel lines (e.g., FIG. 5D, FIG. 5E, and FIG. 6C), or non-parallellines that may, but need not, intersect with other sewn lines. Thestitches may interlace between substrate fibers (fibers, for example, asshown in FIG. 5A), for example, as shown in FIG. 5B, FIG. 5C, FIG. 6A,and FIG. 6B. The stitched lines may comprise interruptions (e.g., breaksbetween lines such that the lines are not continuous) or may becontinuous. The stitched lines may be staggered relative to otherstitched lines.

Stitches and stitch patterns may be sewn (embroidered) into thesubstrate material at any suitable density. The density may provide forhigher surface area coverage and, at least for a period of time, thedensity may also impart strength or reinforcement into the substrate.The stitching density may also make the substrate more resistant tostretching relative to a lower density of stitches. Density may comprisethe number of stitches within a stitch pattern. Density may comprise thenumber of adjacent or parallel stitch patterns and/or the proximity ofadjacent or parallel stitch patterns to each other or other stitchpatterns (e.g., FIG. 5D, FIG. 5E, and FIG. 6C).

Stitch patterns may be overlaid in either the embroidered pattern on thesubstrate and/or the pattern connecting the first and second layers(e.g., substrate and anti-adhesion layers). Thus, for example, a secondstitch pattern (second sub-pattern) may be sewn or embroidered over afirst stitch pattern (first sub-pattern). The filaments (threads, etc.)may be sewn into a pattern comprising a plurality of perpendicular orintersecting lines (e.g., FIG. 7A). Subsequent stitch patterns may besewn in a different direction relative to another stitch pattern. Thusfor example, a second stitch pattern may be sewn into the substratematerial in a direction that is diagonal or perpendicular to thedirection of another stitch pattern sewn into the substrate material.Each set of intersecting lines may be sewn into the substrate materialat any suitable density. For example, one set of lines may be sewn at arelatively high density and another set of lines (the intersecting set)may be sewn at a relatively low density, for example, as shown in FIG.7B. In some aspects, both sets of intersecting lines may be sewn at ahigh density (not shown). The high density line set may be sewn on topof the low density line set (FIG. 7B), or vice versa.

Stitch patterns may comprise parallel straight lines, non-parallelstraight lines, intersecting lines, staggered lines, grids, randomstitching, curves, angled lines, zig-zags, or any combination thereof,any of which may comprise irregular patterns, regular patterns, or acombination of regular and irregular patterns, and any of which maycomprise continuous stitching, interrupted stitching, or a combinationof continuous and interrupted stitching.

Zig-zag patterns may be preferred in some aspects, and each zig-zag maybe sewn with different amplitudes and/or frequencies. FIGS. 8A through8G show examples of suitable stitch patterns. FIG. 8A shows a squaredstitch pattern, with threads 50 are sewn into the substrate 10 as aseries of squares. FIG. 8B shows an example of a basic zig-zag pattern,with FIGS. 8C and 8D showing variations of a zig-zag pattern. In FIG.8C, the zig-zag pattern is sewn at a high density and withlarger-diameter threads. In FIG. 8D, the zig-zag pattern is sewn withdifferent amplitudes and frequencies among the angled stitches. In FIG.8E, a curved stitch pattern is sewn into the substrate material. In FIG.8F, a stitch pattern comprising interrupted stitching is shown sewn intothe substrate material, with the interrupted stitch pattern showinginterrupted zig-zag stitches solely for illustration purposes, as anystitch pattern may comprise interruptions in the continuity of thestitches. In FIG. 8G, a random stitch pattern is shown sewn into thesubstrate material. FIGS. 9A through 9D show a close-up view of thepatterns shown in FIGS. 8A through 8D, respectively, and illustrate thatthe threads interlace throughout the substrate in order to form thestitch pattern.

Stitch patterns may comprise a plurality of angles, which may comprise aplurality of repeating angles (FIGS. 8B to 8D). Where a plurality ofangled lines is employed, they may be sewn/embroidered in parallel or ina grid pattern. The angle is formed between inflection points in thestitch pattern, and each angle may be from about 0 degrees to about 180degrees, or at any integer between 0 degrees and 180 degrees, inclusive(e.g., 1 degrees, 2 degrees, 3 degrees, 4 degrees, 5 degrees, 6 degrees,7 degrees, etc.). It is preferred that the same angle is used throughouta given stitch line, but in some aspects, a combination of differentangles may be used throughout a given stitch line. Thus, by way ofexample and for illustration purposes only a stitch pattern may comprisea plurality of repeating 30 degree angles, or may comprise a pluralityof alternating 30 and 50 degree angles, or may comprise any combinationof angles.

Stitch patterns may comprise a plurality of lines arranged in a patterncomprising a plurality of curves, including a wave pattern, anundulating pattern, a ripple pattern, an oscillating line pattern, orany combination thereof, which may be regular or irregular. A subset ofthe lines in a curve pattern may comprise a different amplitude,frequency, or amplitude and frequency relative to another subset of thelines in a curve in the stitch pattern. When embroidering patterns ontothe substrate, the embroidered pattern may be highly dense (e.g.,covering more than 80%, 85%, 90%, 95%, 98%, 99%, etc. of at least theupper or lower surface of the substrate. Higher density patterns may beparticularly helpful when an additional anti-adhesive layer is notapplied.

In the case of parallel straight stitches or angled stitch patterns,placing such stitch patterns closer together allows for more stitchpatterns to be sewn or embroidered into the substrate. High densityparallel stitch patterns may comprise adjacent stitch patterns placedfrom about 0.5 mm to about 5 mm apart, may comprise adjacent stitchpatterns placed from about 1 mm to about 4 mm apart, from about 1 mm toabout 3.5 mm apart, from about 1 mm to about 3.3 mm apart, from about 1mm to about 3.2 mm apart, from about 1 mm to about 3.1 mm apart, fromabout 1 mm to about 3 mm apart, from about 1 mm to about 2.8 mm apart,from about 1 mm to about 2.6 mm apart, from about 1 mm to about 2.5 mmapart, from about 1 mm to about 2.3 mm apart, from about 1 mm to about 2mm apart, from about 2 mm to about 3.5 mm apart, from about 2 mm toabout 3.3 mm apart, from about 2 mm to about 3.1 mm apart, from about 2mm to about 3 mm apart, from about 2 mm to about 2.8 mm apart, fromabout 2 mm to about 2.5 mm apart, or from about 2 mm to about 2.2 mmapart.

Stitches may be from about 0.5 mm to about 12 mm per stitch. Stitchesmay be from about 1 mm to about 7 mm per stitch, from about 1 mm toabout 6 mm per stitch, from about 1 mm to about 5 mm per stitch, fromabout 2 mm to about 6 mm per stitch, from about 2 mm to about 5 mm perstitch, from about 2 mm to about 4 mm per stitch, from about 3 mm toabout 6 mm per stitch, or from about 3 mm to about 5 mm per stich.

In some aspects, the adhesion barrier material (e.g., threads, etc.) maybe sewn into the substrate in a corner-locked stitch pattern. Suchpatterns are described in in U.S. patent application Ser. No.15/196,439, incorporated by reference herein.

A stitch patterns may be sewn or embroidered through all layers of alayered substrate material. In some aspects, combinations of differentstitch patterns may be sewn or embroidered into different portions ofthe substrate material, for example, to accommodate the direction ororientation or site of implantation.

Anti-Adhesive Materials (Layer 2)

Any of the anti-adhesive materials may be a biologic such as a sheet orsheets of ECM. For example, the sheet of anti-adhesive material may be asheet of extracellular matrix derived from one or more of the dermis,pericardium, peritoneum, intestine, stomach, or forestomach.

Other adhesion barrier materials may include oxidized regeneratedcellulose (ORC). ORC is typically produced by oxidizing the cellulose byexposing the cellulose to nitrogen dioxide or nitrogen tetroxide. See,for example, U.S. Pat. No. 3,364,200. Thus, an adhesion barrier in theform of a sheet, leaf or membrane preferably comprises ORC, such thatthe cellulose is already in oxidized form when the barrier is joined tothe substrate as a substrate-barrier unit.

ORC in the form of a thread, yarn, or filament may be used to sew anadhesion barrier to the substrate and/or to embroider the substrate.Thus, the adhesion barrier material may be sewn to the substrate alreadyin oxidized form. A thread, yarn, or filament of non-oxidized cellulose(e.g., rayon) may be used to sew to the substrate, particularly wherethe non-oxidized form may better withstand the forces applied by asewing machine relative to the oxidized form. A stitch pattern asdescribed or exemplified herein of the cellulose in non-oxidized formmay be sewn into the substrate, and then the substrate and the stitchesmay be oxidized according to any suitable technique such that ORCresults, thereby imparting adhesion barrier properties into the stitchpattern.

FIG. 10A illustrates an example of a portion of a material (such as agraft material) formed as described herein. In this example, theanti-adhesive layer 30 is shown on the top and includes two (thoroughone or more than two sheets may be used) sheets. The sheets are sewninto the substrate (e.g., a mesh) using a pair of threads 72,75 thatinterlock. The resulting stitching pattern forms a plurality of discreteattachment sites 70. In this example, the discrete attachment sites inthe line of stitches are separated from each other by a distance 80. Thestitching pattern may extend along the outer surfaces of the material,and may form an overall attachment pattern such as a grid or any of theother patterns described herein. The attachment pattern flexibly securesthe layers together. When a closed-cell pattern is formed (as shown bythe grid patterns of FIG. 2C, the openings between the grids may have aminimum distance of between about 0.5 mm and 30 mm (e.g., between about1 mm and 30 mm, between about 2 mm and 30 mm, between about 3 mm and 30mm, between about 5 mm and 30 mm, etc.). When an open-cell pattern(e.g., parallel lines, discrete islands, random patterns), the openingsbetween lines of stitching may have a minimum distance of between about0.5 mm and 30 mm (e.g., between about 1 mm and 30 mm, between about 2 mmand 30 mm, between about 3 mm and 30 mm, between about 5 mm and 30 mm,etc.).

FIGS. 11A-C and 12A-C illustrate examples of graft materials having afirst layer stacked onto a second layer. The first layer 10 comprises amesh formed of a non-absorbable material. In FIGS. 12A-12C, the meshincludes a first pattern stitched (embroidered) into the mesh with abioabsorbable material. In this case, the embroidered pattern does notconnect the mesh to another material, but may alter the complianceproperties and/or strength of the material, as discussed above. Thesecond layer 30 comprises an anti-adhesive material comprising aplurality of sheets 25, 25′ (two are shown) of extracellular matrixmaterial (ECM). The second layer is flexibly attached to the first layerwith a second pattern 110 of discrete stitched attachment sites (visibleon the back surface of the graft, shown in FIG. 12C). In FIGS. 12A-12C,the second pattern of discrete stitched attachment sites is less densethan the first pattern 115 stitched into the mesh, wherein adjacentdiscrete attachment sites are separated by a distance of between 0.5 mmand 30 mm and wherein adjacent regions of the first layer and secondlayer between the discrete attachment sites may slide relative to eachother. FIGS. 11B and 12B show the “top” of the grafts, while FIGS. 11Cand 12C show the “bottom” (opposite) sides.

FIGS. 13A-13B illustrate a substrate 131 material shown as anopen-celled mesh. This this example, the mesh is a polypropylene meshhaving an open cell pore of between 0.5 mm and 6 mm diameter. Thefilaments forming the mesh may have a diameter of between 0.001 inch and0.010 inches. This mesh may be reinforced with an embroidered pattern ofa bioabsorbable material, as shown in FIG. 13B. In this example, thepattern comprises a pair of grid sub-patterns 133 that are rotated at45° relative offset.

The mesh shown in FIGS. 13A and 13B may be attached via an attachmentpattern to an anti-anti-adhesive material as shown in FIGS. 14A-14B.FIG. 14A shows the top or front side of the graft material showing boththe mesh 131 with the embroidered pattern 133 as shown in FIG. 13B, butalso shows the attachment pattern of stitches forming the plurality ofdiscrete attachment sites between the two layers. FIG. 14B shows theopposite (back) side of the graft of FIG. 14A, showing the attachmentpattern corresponding to the discrete attachment sites sewn to flexiblysecure the two layers together. This arrangement of discrete attachmentsites does not modify the compliance of the overall materialsubstantially (e.g. less than 15%, less than 13%, less than 11%, lessthan 10%, etc.), and may allow the two layers to slide relative to eachother, particularly in the regions between the attachment sites 149.

As mentioned, the overall compliance of the material may be controlledand may provide advantages compared to other materials, particularlywhen inserted into the body as a graft. The manner of attachment betweenthe substrate and the anti-adhesion material may be particularlyimportant. In general, it is desirable that the attachment between thetwo layers does not increase the stiffness (decrease compliance)substantially. For example, in FIG. 15A, the graph shows a comparisonbetween materials having different substrate attached. On the far left,the first bar corresponds to a material in which the substrate (mesh)layer is attached to the anti-adhesion layer (e.g., ECM) by an adhesiveor glue. In this case, the overall compliance changes substantiallycompared to the compliance of either the substrate, the ECM or a loose(unattached) stack of the two, typically >30% (e.g., between 20% and70%). In contrast, a material in which small, discrete islands (“spots”)of adhesive are used to attach the Mesh to the ECM layer (shown in thesecond bar), the compliance changes less than 15%. A similar result isfound with ECM stitched at low density as described herein, and even atrelatively higher densities.

In addition, it may also be generally beneficial to reduce the number ofattachment sites between the layers, as this may impact adhesionformation to the implant. As shown in FIG. 15B the likelihood of formingan adhesion increases (relatively low to relatively high) as the densityof attachment sites increases. In this example, the density correspondsto a stitch density (and may correspond to the amount to exposedthread/polymer material on the surface of the graft). The stitchingpattern shown is in a 2-layer (e.g., 2 ECM sheet) embodiment in whichthe attachment pattern of discrete attachment sites is a stitched gridpattern having grid spacing of between 25 and 1 mm.

Similarly, FIGS. 15C and 15D illustrate the effect of attachment sitedensity (e.g., stitch density) on compliance for different stitchpatterns and different layer numbers of ECM (anti-adhesion material).FIG. 15C shows the relative compliance in layered closed-cell attachmentpatterns, while FIG. 15D shows a similar relationship in layeredopen-cell patterns. The closed-cell patterns may also benefit fromhaving increase strength due to the attachment pattern.

In any of these apparatuses (e.g., grafts) described herein, it may beparticularly beneficial to match the compliance properties of thematerial to the body, especially at implantation time. Over time in thebody, this compliance may change (preferably increase) to preventstiffening and discomfort due to compliance increase as the implantbecomes ingrown and/or scarred. FIG. 16 illustrates the percentcompliance strain at 16 N/cm of the mesh alone (far left), theembroidered mesh, the embroidered mesh with ECM stitched at low density,and an embroidered mesh with ECM laminated on. It is desirable, based onclinical and experimental data, to have the percent compliance strain at16 N/cm be between 10% and 30% 157, at least at implantation. Asindicated the meshes described herein (and particularly the embroideredmesh with ECM stitched at low density) is within this desired compliancewindow, in contrast to variations in which the anti-adhesion material islaminated or attached at high density.

As used herein, “inhibiting” includes reducing, decreasing, blocking,preventing, delaying, stopping, and/or down regulating. By way ofexample, but not of limitation, inhibiting adhesions includes reducingadhesion formation.

When a feature or element is herein referred to as being “on” anotherfeature or element, it can be directly on the other feature or elementor intervening features and/or elements may also be present. Incontrast, when a feature or element is referred to as being “directlyon” another feature or element, there are no intervening features orelements present. It will also be understood that, when a feature orelement is referred to as being “connected”, “attached” or “coupled” toanother feature or element, it can be directly connected, attached orcoupled to the other feature or element or intervening features orelements may be present. In contrast, when a feature or element isreferred to as being “directly connected”, “directly attached” or“directly coupled” to another feature or element, there are nointervening features or elements present. Although described or shownwith respect to one embodiment, the features and elements so describedor shown can apply to other embodiments. It will also be appreciated bythose of skill in the art that references to a structure or feature thatis disposed “adjacent” another feature may have portions that overlap orunderlie the adjacent feature.

Terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention.For example, as used herein, the singular forms “a”, “an” and “the” areintended to include the plural forms as well, unless the context clearlyindicates otherwise. It will be further understood that the terms“comprises” and/or “comprising,” when used in this specification,specify the presence of stated features, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneor more other features, steps, operations, elements, components, and/orgroups thereof. As used herein, the term “and/or” includes any and allcombinations of one or more of the associated listed items and may beabbreviated as “/”.

Spatially relative terms, such as “under”, “below”, “lower”, “over”,“upper” and the like, may be used herein for ease of description todescribe one element or feature's relationship to another element(s) orfeature(s) as illustrated in the figures. It will be understood that thespatially relative terms are intended to encompass differentorientations of the device in use or operation in addition to theorientation depicted in the figures. For example, if a device in thefigures is inverted, elements described as “under” or “beneath” otherelements or features would then be oriented “over” the other elements orfeatures. Thus, the exemplary term “under” can encompass both anorientation of over and under. The device may be otherwise oriented(rotated 90 degrees or at other orientations) and the spatially relativedescriptors used herein interpreted accordingly. Similarly, the terms“upwardly”, “downwardly”, “vertical”, “horizontal” and the like are usedherein for the purpose of explanation only unless specifically indicatedotherwise.

Although the terms “first” and “second” may be used herein to describevarious features/elements (including steps), these features/elementsshould not be limited by these terms, unless the context indicatesotherwise. These terms may be used to distinguish one feature/elementfrom another feature/element. Thus, a first feature/element discussedbelow could be termed a second feature/element, and similarly, a secondfeature/element discussed below could be termed a first feature/elementwithout departing from the teachings of the present invention.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising” means various components can be co-jointlyemployed in the methods and articles (e.g., compositions and apparatusesincluding device and methods). For example, the term “comprising” willbe understood to imply the inclusion of any stated elements or steps butnot the exclusion of any other elements or steps.

In general, any of the apparatuses and methods described herein shouldbe understood to be inclusive, but all or a sub-set of the componentsand/or steps may alternatively be exclusive, and may be expressed as“consisting of” or alternatively “consisting essentially of” the variouscomponents, steps, sub-components or sub-steps.

As used herein in the specification and claims, including as used in theexamples and unless otherwise expressly specified, all numbers may beread as if prefaced by the word “about” or “approximately,” even if theterm does not expressly appear. The phrase “about” or “approximately”may be used when describing magnitude and/or position to indicate thatthe value and/or position described is within a reasonable expectedrange of values and/or positions. For example, a numeric value may havea value that is +/−0.1% of the stated value (or range of values), +/−1%of the stated value (or range of values), +/−2% of the stated value (orrange of values), +/−5% of the stated value (or range of values), +/−10%of the stated value (or range of values), etc. Any numerical valuesgiven herein should also be understood to include about or approximatelythat value, unless the context indicates otherwise. For example, if thevalue “10” is disclosed, then “about 10” is also disclosed. Anynumerical range recited herein is intended to include all sub-rangessubsumed therein. It is also understood that when a value is disclosedthat “less than or equal to” the value, “greater than or equal to thevalue” and possible ranges between values are also disclosed, asappropriately understood by the skilled artisan. For example, if thevalue “X” is disclosed the “less than or equal to X” as well as “greaterthan or equal to X” (e.g., where X is a numerical value) is alsodisclosed. It is also understood that the throughout the application,data is provided in a number of different formats, and that this data,represents endpoints and starting points, and ranges for any combinationof the data points. For example, if a particular data point “10” and aparticular data point “15” are disclosed, it is understood that greaterthan, greater than or equal to, less than, less than or equal to, andequal to 10 and 15 are considered disclosed as well as between 10 and15. It is also understood that each unit between two particular unitsare also disclosed. For example, if 10 and 15 are disclosed, then 11,12, 13, and 14 are also disclosed.

Although various illustrative embodiments are described above, any of anumber of changes may be made to various embodiments without departingfrom the scope of the invention as described by the claims. For example,the order in which various described method steps are performed mayoften be changed in alternative embodiments, and in other alternativeembodiments one or more method steps may be skipped altogether. Optionalfeatures of various device and system embodiments may be included insome embodiments and not in others. Therefore, the foregoing descriptionis provided primarily for exemplary purposes and should not beinterpreted to limit the scope of the invention as it is set forth inthe claims.

The examples and illustrations included herein show, by way ofillustration and not of limitation, specific embodiments in which thesubject matter may be practiced. As mentioned, other embodiments may beutilized and derived there from, such that structural and logicalsubstitutions and changes may be made without departing from the scopeof this disclosure. Such embodiments of the inventive subject matter maybe referred to herein individually or collectively by the term“invention” merely for convenience and without intending to voluntarilylimit the scope of this application to any single invention or inventiveconcept, if more than one is, in fact, disclosed. Thus, althoughspecific embodiments have been illustrated and described herein, anyarrangement calculated to achieve the same purpose may be substitutedfor the specific embodiments shown. This disclosure is intended to coverany and all adaptations or variations of various embodiments.Combinations of the above embodiments, and other embodiments notspecifically described herein, will be apparent to those of skill in theart upon reviewing the above description.

What is claimed is:
 1. A hernia repair graft comprising: a first layerstacked onto a second layer; wherein the first layer comprises: a meshand a first pattern embroidered into the mesh; wherein the second layercomprises a sheet of anti-adhesive material comprising an extracellularmatrix (ECM) material; further wherein the second layer is flexiblyattached to the first layer with a plurality of discrete attachmentsites, wherein adjacent regions of the first layer and second layerbetween the discrete attachment sites may slide relative to each other.